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Breast Carcinomas Arising at a Young
Age: Unique Biology or a Surrogate
for Aggressive Intrinsic Subtypes?
TO THE EDITOR: In the July 10, 2008 issue of Journal of Clinical
Oncology,
1
we reported a large-scale genomic analysis illustrating that
mRNA expression levels of key breast cancer-associated genes, ER-
,
ER-
, epithelial growth factor receptor (EGFR), and human epider-
mal growth factor receptor 2 (HER2) occurred in an age-related man-
ner. Moreover, when stratified by age, breast tumors arising in
younger women ( 45 years) were enriched with 350 biologically
relevant gene sets compared with those arising in older women ( 65
years).
2
Breast cancer is no longer viewed as a single disease, but rather
a compilation of several distinct subtypes defined via gene expression
analysis.
2
Microarray techniques have divided breast cancer into in-
trinsic subtypes: luminal A, luminal B, HER2-enriched, and basal-like,
each with unique prognostic and therapeutic implications.
3,4
On the
basis of findings from Carey et al,
5
we hypothesized that (1) breast
tumors arising in younger women may be more enriched for aggres-
sive subtypes and (2) age-specific biologic differences observed in
breast carcinomas may be highly subtype dependent. To evaluate the
relationship between age and breast cancer subtype, and to account for
potential confounding variables not previously included, we have
performed new analyses on data from Anders et al
1
and include a
similar analysis performed on a second independent microarray-
based breast tumor data set.
To explore our hypotheses, we chose to reanalyze our previous
data set; however, we limited our current analyses to a combination of
two of the four large data sets used previously, genomic spatial event
(GSE) 4922
6
and GSE7849,
7
termed data set A. Please note that two of
the four previous data sets were excluded (GSE2034
8
and GSE3143
9
)
because they lacked complete clinical data (ie, histologic grade). Our
first goal was to define the distribution of intrinsic subtypes assigned
by the PAM50
10
to determine whether subtype correlated with age
distinction. We hypothesized that more aggressive subtypes (ie, basal-
like) would be over-represented among breast carcinomas arising in
younger women ( 45 years), whereas older women ( 65 years)
would more commonly be diagnosed with luminal tumors.
5
As ex-
pected, there was a significant association between subtype and age
(P 3.8e-06; Table 1). Specifically, a higher proportion of younger
women were diagnosed with basal-like (odds ratio [OR], 12.27; 95%
CI, 3.96 to 45.0) and HER2-enriched (OR, 4.63; 95% CI, 1.50 to 16.48)
breast tumors.
Recognizing that age-specific differences in subtype distribu-
tion were present, we next examined other potential confounding
variables and noted that grade and sample source were associated
with age (Table 1). We hypothesized that accounting for all significant
Table 1. Age-Specific Clinical Characteristics of Data Set A (GSE4922 and GSE7849; age 45 and 65 years)
Characteristic
All (N 192)
Younger
( 45;
n 48)
Older
( 65;
n 144)
Odds Ratio P 95% CINo. % No. % No. %
Estrogen receptor
Positive 156 83 38 81 118 84 1.28 .58 0.51 to 2.96
Negative 31 17 9 19 22 16 1.00 NA NA
Nodal status
Positive 57 31 17 35 40 30 0.77 .46 0.38 to 1.57
Negative 126 69 31 65 95 70 1.00 NA NA
Tumor size
2 cm 109 57 23 48 86 60 1.00 NA NA
2 cm 83 43 25 52 58 40 0.62 .16 0.32 to 1.20
Histologic grade
1 41 22 6 13 35 25 0.31 .015 0.10 to 0.80
2 82 44 16 36 66 47 0.43 .025 0.20 to 0.90
3 63 34 23 51 40 28 1.00 NA NA
Subtype (PAM50)
Lum A 51 27 5 13 46 38 1.00 NA NA
Lum B 46 24 5 13 41 34 1.12 .87 0.28 to 4.45
HER2 35 18 12 31 23 19 4.63 7.0e-03 1.50 to 16.48
Basal 29 15 17 44 12 10 12.27 5.2e-06 3.96 to 45.0
Normal 31 16 9 19 22 15 3.65 .033 1.11 to 13.50
Source
GSE4922 156 81 33 69 123 85 1.00 NA NA
GSE7849 36 19 15 31 21 15 0.38 .015 0.17 to 0.83
Abbreviations: NA, not available; PAM, prediction analysis of microarray; Lum, luminal; HER2, human epidermal growth factor receptor 2; GSE, genomic spatial event.
JOURNAL OF CLINICAL ONCOLOGY
CORRESPONDENCE
VOLUME 29 NUMBER 1 JANUARY 1 2011
e18 © 2010 by American Society of Clinical Oncology
Journal of Clinical Oncology, Vol 29, No 1 (January 1), 2011: pp e18-e20
Page 1

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